The invention pertains to novel 3-alkoxybenzylpiperidine derivatives (i.e., amides and ureas of 3- and 4-benzylpiperidines) having drug and bio-affecting properties and to their preparation, pharmaceutical formulations containing them, and methods of use. In particular, the invention concerns N-acyl 3-benzylpiperidines and N-amido 4-benzylpiperidines having a meta-alkoxy substituent in the phenyl ring of the benzyl moiety. These compounds possess melatonergic properties that should make them useful in treating certain medical disorders.
Melatonin (i; N-acetyl-5-methoxytryptamine) is a hormone which is synthesized and secreted primarily by the pineal gland. Melatonin levels show a cyclical, circadian pattern with highest levels occurring during the dark period of a circadian light-dark cycle. Melatonin is involved in the transduction of photoperiodic information and appears to modulate a variety of neural and endocrine functions in vertebrates, including the regulation of reproduction, body weight and metabolism in photoperiodic mammals, the control of circadian rhythms, and the modulation of retinal physiology. ##STR1##
Recent evidence demonstrates that melatonin exerts its biological effects through specific receptors. Use of the biologically active, radiolabelled agonist [.sup.125 I]-2-iodomelatonin has led to the identification of high affinity melatonin receptors in the central nervous systems (CNS) of a variety of species. The sequence of one such high affinity melatonin receptor, cloned from frog melanocytes, has been reported. In mammalian brain, autoradiographic studies have localized the distribution of melatonin receptors to a few specific structures.
Although there are significant differences in melatonin receptor distribution between closely related species, in general the highest binding site density occurs in discrete nuclei of the hypothalamus. In humans, specific [.sup.125 I]-2-iodomelatonin binding within the hypothalamus is completely localized to the suprachiasmatic nucleus, strongly suggesting the melatonin receptors are located within the human biological clock.
Exogenous melatonin administration has been found to synchronize circadian rhythms in rats (Cassone, et al., J. Biol. Rhythms, 1:219-229, 1986). In humans, administration of melatonin has been used to treat jet-lag related sleep disturbances, considered to be caused by desynchronization of circadian rhythms (Arendt, et al., Br. Med. J. 292:1170, 1986). Further, the use of a single dose of melatonin to induce sleep in humans has been claimed by Wurtman in International Patent Application WO 94/07487. Thus, melatonin agonists should be particularly useful for the treatment of sleep disorders and other chronobiological disorders. Melatonin agonists would also be useful for the further study of melatonin receptor interactions as well as in the treatment of conditions affected by melatonin activity, such as depression, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, immune disorders, neuroendocrine disorders, and a variety of sleep disorders.
Aside from simple indole derivatives of melatonin itself, various amide structures have been prepared and their use as melatonin ligands disclosed. In general these amide structures can be represented as: ##STR2## wherein Z is an aryl or heteroaryl system attached by a two carbon chain to the amide group. Some specific examples follow.
Yous, et al. in European Patent Application EPA 527 687A disclose as melatonin ligands arylethylamines 1, ##STR3## wherein Ar' is, inter alia, a substituted or unsubstituted benzo[b]thiophen-3-yl, benzimidazol-1-yl, benzo[b ]furan-3-yl, 1,2-benzisoxazol-3-yl, 1,2-benzisothiazol-3-yl, or indazol-3-yl radical; R.sub.1 is, inter alia, an alkyl or cycloalkyl group; and R.sub.2 is hydrogen or lower alkyl.
Horn and Dubocovich in European Patent Application EPA 420 064A disclose 2-amidotetralins 2 as melatonin ligands, ##STR4## wherein R.sub.1 is, inter alia, hydrogen, lower alkyl, or lower alkoxyl; R.sub.2 is, inter alia, hydrogen, halogen, or lower alkoxyl; R.sub.3 is, inter alia, hydrogen, or lower alkyl; R.sub.4 is, inter alia, lower alkyl, haloalkyl or cycloalkyl; and R.sub.5 is hydrogen, hydroxyl, halogen, oxo, aryl, lower alkyl or alkylaryl.
Yous, et al. in European Patent Application 506 539A claim melatonin ligands 3, ##STR5## wherein A is oxygen or sulfur; X is a methylene group or a bond; and R is H or lower alkyl when p is 1 and B is defined by the radical 4, ##STR6## wherein R.sub.1 is hydrogen or lower alkyl and R.sub.2 is, inter alia, hydrogen, lower alkyl or cycloalkyl. Alternatively, R is defined by the radical 4 when p is 0 or 1 and B is lower alkoxy.
Several naphthalene derivatives have also been disclosed as melatonin ligands. Andrieux, et al. in European Patent Application 447 285A claim amidoalkylnaphthalenes 5. ##STR7## wherein R is lower alkyl; R.sub.1 is hydrogen or lower alkyl; and R.sub.2 is, inter alia, hydrogen, lower alkyl, or cycloalkyl.
Yous, et al. in European Patent Application 562 956A disclose amide and urea naphthalene derivatives 6, ##STR8## in which R is hydrogen or OR.sub.4 wherein R.sub.4 is, inter alia, hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl; R.sub.1 is hydrogen or COOR.sub.5 wherein R.sub.5 is hydrogen or alkyl; R.sub.2 is hydrogen or alkyl; X is NH or a bond; and R.sub.3 is, inter alia, alkyl, alkenyl, or cycloalkyl.
Lesieur, et al. in European Patent Application 530 087A disclose naphthylethylureas and naphthylethylthioureas 7, ##STR9## in which R is hydrogen or OR.sub.3 wherein R.sub.3 is, inter alia. hydrogen, lower alkyl, or cycloalkyl; R.sub.1 is hydrogen or lower alkyl; X is oxygen or sulfur; and R.sub.2 is, inter alia, lower alkyl or cycloalkyl.
Finally, Langlois, et al., in Australian Patent Application AU-A-48729/93 disclose arylalkyl(thio)amides 8 as melatonergic ligands, ##STR10## wherein R.sub.1 is hydrogen or lower alkyl; R.sub.2 is hydrogen, halogen, or lower alkyl; R.sub.3 and R.sub.4 are identical or different groups including, inter hydrogen, halogen, or lower alkyl; R.sub.5 is hydrogen or lower alkyl; X is sulfur or oxygen and R.sub.7 is, inter alia, lower alkyl or alkenyl.
However these references do not teach or suggest the novel melatonergic alkoxybenzylpiperidine derivatives of the present invention. There are few reported examples of compounds bearing an alkoxy-substituted benzyl moiety appended to the 3- or 4-position of an N-acyl piperidine. Begue and Fetizon describe the synthesis of bridged piperidine derivatives 9 in Bull. Soc. Chim. Fr., 1969, pp. 781-787. ##STR11##
Jacobs et al. in European Patent Application 532177A disclose compounds of type 10 as intermediates in the synthesis of 11. Neither 9 nor 10 were described as having melatonergic properties. ##STR12##